Thiopurine Enhanced Mutations for PD-1/Ligand-1 Efficacy

The TEMPLE study is a single-center prospective phase Ib and II trial to determine the safety, tolerability and efficacy of Atezolizumab given in combination with thiopurine therapy (6-mercaptopurine and 6-thioguanine) in patients with advanced and/or metastatic solid tumors with an intermediate tumor mutational burden. Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) will be determined in a single armed, open label phase Ib trial with a fixed dose of Atezolizumab in combination with thiopurine therapy with a dose-limiting toxicity (DLT) period of 4 weeks. A total of 27-39 patients will be enrolled in the TEMPLE study. Phase Ib will enroll 3-18 patients depending on the number of DLTs and need for dose de-escalation. Data from patients treated in the phase Ib study at RP2D will be included when assessing endpoints in the phase II part of the study. Phase II will enroll a total of 27 patients (including 3-6 patients treated at RP2D in the phase I part of the trial) in a Simon's 2 stage design (13 in stage 1 and 14 in stage 2).

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized treatment of several cancer types. However, many patients fail to respond. A prerequisite for response is the presence of neoepitopes on cancer cells that trigger the immune system, and the likelihood hereof increases with the number of mutations in the cancer. The thiopurines 6-mercaptopurine (6MP) and 6-thioguanine (6TG) are prodrugs that are converted into cytotoxic metabolites that are incorporated into DNA (DNA-TG) and cause DNA-damage through futile DNA mismatch repair attempts. 6MP and 6TG have been used for more than 50 years for long-term treatment of hematological cancers. In leukemia, high levels of DNA-TG are associated with higher cure rates. A recent pilot study has shown that combination therapy with 6MP and 6TG significantly increases DNA-TG levels and that the drug combination is safe and tolerable. The higher DNA-TG levels most likely increase the mutational burden and thus presence of neoepitopes that activate cytotoxic T-cell responses. The TEMPLE project will apply the innovative thiopurine combination strategy to increase the mutational burden, presence of neoepitopes and thus proportion of patients with incurable solid cancers that respond to treatment with ICIs. STUDY DESIGN: The TEMPLE study is a single-center prospective phase Ib and II trial to determine the safety, tolerability and efficacy of Atezolizumab given in combination with thiopurine therapy in patients with advanced and/or metastatic solid tumors with an intermediate tumor mutational burden. Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) will be determined in a single armed, open label phase Ib trial with a fixed dose of Atezolizumab in combination with thiopurine therapy. In the phase Ib part of the study, patients will start treatment with investigational medicinal products: 1. 6-mercaptopurine (6MP) 50 mg/m2 orally taken once a day, 2. 6-thioguanine (6TG) 12.5 mg/m2 orally taken once a day, and 3. Atezolizumab 1200 mg every 3 weeks The combination of thiopurines and Atezolizumab will be administered in 21-day cycles. The DLT evaluation period will be four weeks. Patients will be included in a modified 3+3 design. 3-18 patients are expected to be enrolled in the phase Ib study, depending on observed DLTs. Phase II be an open label, single arm phase II trial enrolling additional patients up to a total of 27 patients treated at RP2D in a Simon's 2 stage design (13 in stage 1 and 14 in stage 2). All three study drugs are already approved for within hospital use in Denmark and the Summary of Product Characteristics (SmPCs) will be used in assessment of possible undesirable effects during the study. Patients will be monitored closely for adverse events using the NCI CTCAE v 5.0. If patients develop toxicity, the dose may be modified or discontinued. All dosing interruptions and modifications should be based on the worst preceding toxicity. Patients will be monitored continuously, and dose modifications or interruptions will occur based on the observed toxicity. For Atezolizumab, no dose reduction is permitted, but infusions may be omitted. Dose modifications may be implemented to manage toxicities for 6MP and 6TG. Patients will continue treatment until progression disease, death, development of unacceptable toxicity or withdrawal of consent. Patients can be treated for a maximum of 2 years with option to re-challenge upon progression or relapse for those responding.